Verteporfin - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Ophthalmic products

Included in the formulation

Visudin®

lyophilizate in / in

Novartis Pharma AG Switzerland

АТХ:

S.01.L.A Preparations preventing neovascularization

S.01.L.A.01 Verteporfin

Pharmacodynamics:

The drug for photodynamic therapy in ophthalmology. It is a derivative of benzoporphyrin (BPD-MA), consisting of a mixture of equally active stereoisomers BPD-MAC and BPD-MAD in a 1: 1 ratio.

Verteporfin - photosensitizer, when activated by light, it produces cytotoxic agents only in the presence of oxygen. When energy absorbed by porphyrin is transferred to oxygen, a highly active short-lived singlet oxygen. Singlet oxygen destroys biological structures within the diffuse zone, which leads to local obstruction of the vessels, destruction of cells and, under certain conditions, cell death.

Verteporfin in the recommended dosage is not cytotoxic.

In the plasma verteporfin is transferred primarily to low-density lipoproteins. The selectivity of photodynamic therapy with verteporfin is based, in addition to localized exposure to light, on the selectivity, rapid uptake and accumulation of verteporfin by rapidly proliferating cells, including the endothelium of newly formed retinal vessels. It is assumed that this accumulation is due to the increased sensitivity of receptors in proliferating cells.In tests on rabbits and monkeys with the newly formed vessels of the eye and in clinical trials with intravenous verteporfin, followed by irradiation of laser light having a wavelength of 689 nm was marked by selective occlusion of the newly formed blood vessels, while wide, normal retinal blood vessels remain open. The occlusion of newly formed regional vessels as a result of drug therapy was confirmed by fluorescent angiography.

Pharmacokinetics:

Suction

After intravenous administration of the drug for 10 min in doses of 6 mg / m² and 12 mg / m² surface of the body C_max is 1.5 μg / ml and 3.5 μg / ml, respectively.

For both stereoisomers, the values of C_max and AUC are proportional to dosage. The values of C_max at the end of the injection member to BPD-MAD, than BPD-MAC, which can be due to a more rapid transfer of BPD-MAD from the lipid carrier to lipoproteins. The AUC values for both stereoisomers are similar.

Distribution

Distribution verteporfin after bolus injection at the recommended dosage (usually well tolerated) can vary and, therefore, affect the optimal performance of the laser irradiation.

Proliferating cells delay respectively higher amounts of the drug.Studies of distribution in the eyes of primates using angiography have shown that verteporfin is absorbed selectively and rapidly by newly formed regional vessels of the eye and to a lesser extent by the retinal pigment epithelium. Other eye structures delay only small amounts of the drug.

90% of verteporfin binds to plasma proteins and 10% - to blood cells. In human blood plasma, 90% of verteporfin is associated with lipoprotein fractions and about 6% with albumin. V_d is 0.5 l / kg.

Metabolism

5-10% of the initial dose of verteporfin is metabolized by hydrolysis of its ester group to the diacid of the benzoporphyrin derivative (BPD-DA), which also has photosensitizing activity.

Excretion

The half-life in plasma is approximately 6-7 hours for BPD-MAC and about 4-6 hours for BPD-MAD. Excretion is carried out mainly with bile.

In rats, approximately 90% of the dose of verteporfin for intravenous administration¹⁴C-BPD-MA was excreted with feces in 7 days. Less than 1% of the labeled drug was found in the urine.

Pharmacokinetics in special clinical cases

Average the half-life of BPD-MAD is approximately 6.5 hours in people with chronic viral hepatitis and about 4.7 hours in people who do not have liver disease (statistically significant difference, p <0.05).In people with liver disease, the mean AUC is 1.5 times higher than in healthy volunteers who do not suffer from this pathology. This difference is not clinically significant and does not require correction of doses for patients with mild violations of liver function. Studies of patients with moderate and severe liver disease have not been conducted.

Indications:

- age-related macular degeneration in patients with predominantly classical subfoveolar choroidal neovascularization;

- repeated subfoveolary choroidal neovascularization in pathological myopia.

ICD-10

VII.H30-H36.H35.3 Degeneration of the macula and posterior pole

VII.H30-H36.H35.8 Other specified retinal disorders

VII.H49-H52.H52.1 Myopia

Contraindications:

Porphyria; hepatitis of severe course; lactation period (breastfeeding); hypersensitivity to verteporfinu or any of the components of the drug.

Carefully:

Caution should be given to patients with moderate or severe liver disease, since there is no experience with such patients.

Intravenous injection should be carried out carefully. Verteporfin can cause severe pain, inflammation, soft tissue swelling, or discoloration of the skin in the injection zone. To eliminate pain, analgesics may be required. If subcutaneous hematoma is formed, the injection should be stopped immediately and a cold compress applied to the injection site. The affected area should be carefully protected from direct bright light until soft tissue swelling and discoloration of the skin take place.

Pregnancy and lactation:

The use of the drug during pregnancy is contraindicated.

It is necessary to abandon breastfeeding for at least 48 hours after therapy with verteporfinom.

Dosing and Administration:

The drug is dissolved in 7 ml of water for injection to obtain 7.5 ml of a solution at a concentration of 2 mg / ml. For a dose of 6 mg / m² the body surface should be diluted with the required amount of the drug solution with 5% glucose solution for injection to a final volume of 30 ml.

The drug is administered in 2 stages.

First step - intravenous injection of verteporfin for 10 min at a dose of 6 mg / m² the surface of the body (diluted in 30 ml of injection solution).

Second phase - Activation of the drug with light 15 minutes after the start of the injection.To this end, non-thermal red light (wavelength 689 nm) generated by the laser is directed to a choroidal neovascular lesion using an optical fiber device mounted in a slit lamp using appropriate contact lenses. At a recommended light intensity of 600 mW / cm² to achieve the required radiation dose of 50 J / cm² it takes 83 seconds.

The largest linear size of a choroidal neovascular lesion is determined by fluorescence angiography and eye fundus images. The light beam should affect all newly formed blood vessels and / or zones that block fluorescence. To ensure that the treatment will be subjected to the entire lesion of the retina with poorly expressed boundaries, coverage of the affected area should be increased by 500 μm around the perimeter. The nasal border of the treatment zone should be at least 200 μm from the temporal edge of the optic disc. When treating a lesion whose size exceeds the possible irradiation zone, the light beam should be directed to the most severely damaged areas of the retina.

To obtain the optimal therapeutic effect, it is important to follow the above recommendations.

If treatment is necessary to expose both eyes, light exposure to the other eye should be performed immediately after irradiation of the first eye, but no later than 20 minutes after the start of the injection.

Patients should be examined every 3 months. In case of relapses choroidal neovascularization treatment with the drug must be repeated.

Side effects:

In placebo-controlled clinical trials in patients with age-related macular degeneration and pathological myopia, the following undesirable reactions, possibly associated with the use of the drug, were noted. In most cases, adverse reactions were minor and of a temporary nature. The following criteria for assessing the incidence of adverse events were used: often 1-10%, rarely 0.1-1%.

From the side of the organ of vision: often - such visual impairments as fogging, blurring or flashes of light, reduced visual acuity, visual field defects (gray or dark halos, scotoma and black dots).

A marked decrease in visual acuity (by 4 lines or more on the ETDRS optotype) within 7 days after application of the drug was noted in 2.1% of patients.In most cases, such a decrease in visual acuity was detected in patients with age-related macular degeneration and latent choroidal neovascularization. Later, some patients had partial recovery of visual acuity. Rarely - detachment of the retina (non-regenerated genesis), subretinal and retinal hemorrhages, hemophthalmia. With a frequency of less than 0.1%, there was a disturbance of blood flow in the retina and choroid vessels, detachment of retinal pigment epithelium.

Reactions at the site of administration: often - pain, swelling of soft tissues, inflammation, subcutaneous hematoma; rarely - hemorrhages, discoloration of the skin in the injection zone, hypersensitivity. With a frequency of less than 0.1%, the formation of blisters on the skin at the injection site was noted.

On the part of the body as a whole: often - back pain during the injection, photosensitive reactions, asthenia. Rarely - hypertension, hypoesthesia, nausea and fever. With a frequency of less than 0.1%, vasovagal reactions, hypersensitivity reactions (in rare cases of severe course), including headache, discomfort, fainting, increased sweating, dizziness, rash, urticaria, pruritus, dyspnea, hyperemia, changes in blood pressure and heart rate abbreviations.Light-sensitive reactions were noted in 2.2% of patients and were expressed in the form of a sunburn, usually occurring on the first day after the injection of the drug. To prevent light-sensitive reactions, follow the instructions for protection against light exposure. The development of back pain in patients was not associated with hemolysis or allergic reactions. As a rule, the pain disappeared soon after the end of the drug. The pains arising in the introduction of the drug in the back and chest had different irradiation (for example, in the humeral girdle, pelvic region).

Overdose:

Symptoms: there were no cases of drug overdose. An overdose of the drug and / or light exposure to the treated eye can lead to indiscriminate disruption of the blood supply to normal retinal vessels with the possible sharp decrease in vision, prolonging the period of photosensitization of the patient for several days. At a dosage of about 20 mg / m², that is 3 times higher than the normal dose, the period of photosensitization is increased to 6-7 days.

Treatment: In such cases, the patient should extend the skin and eye protection time from exposure to direct sunlightlight or bright lighting indoors in accordance with the amount of the overdosed drug.

Interaction:

There were no special studies on drug interaction in humans. Based on the mechanism of action, some drugs may affect the effect of drug treatment.

Joint application other photosensitizing drugs (such as tetracyclines, sulfonamides, phenothiazines, hypoglycemic drugs - derivatives of sulfonylureas, thiazide diuretics and griseofulvin) may increase the risk of developing photosensitive reactions.

It can be expected that connections connecting the active oxygen or radicals, such as dimethylsulfoxide, betacarotene, ethanol, formate and mannitol, reduce the activity of verteporfin.

Calcium channel blockers, polymyxin B or radiation therapy may increase the degree of absorption of verteporfin by the vascular endothelium.

Anticoagulants, vasoconstrictors or antiplatelet agents, such as thromboxane A2 inhibitors, can reduce the effectiveness of vetreporphin.

The drug is precipitated in saline solutions.Do not use saline or other parenteral solutions for dissolution and dilution. Do not dissolve verteporfin in one solution with other drugs. The solution must be protected from direct sunlight.

Special instructions:

Patients taking the drug remain photosensitized within 48 hours after the injection. In the first 48 hours after therapy, patients should avoid exposure to exposed skin and eyes of sunlight and bright artificial light. If patients need to go out in the daytime during the first 48 hours after therapy, they should protect the skin with light-tight clothing, and eyes - with dark glasses. Indoor light is not dangerous. Patients should not be in the dark, they should be in a lighted room, as light inside the room helps to remove the drug through the skin. UV-protective creams are not effective in protecting against the development of photosensitive reactions.

Patients with a marked decrease in visual acuity (up to 40% or more) during the first week after treatment, a second course can be prescribed only if the vision is restored to the level preceding the treatment.The attending physician is obliged to carefully evaluate the ratio of potential benefits to risks from therapy.

In patients with predominantly latent macular degeneration (> 50% of the lesion), the effect of treatment was not revealed in the intermediate analysis in the III clinical phase.

Intravenous injection should be carried out carefully. The substance can cause severe pain, inflammation, soft tissue swelling, or discoloration of the skin in the injection zone. To eliminate pain, analgesics may be required. If subcutaneous hematoma is formed, the injection should be stopped immediately and a cold compress applied to the injection site. The affected area should be carefully protected from direct bright light until soft tissue swelling and discoloration of the skin take place.

Clinical data on the administration of the drug to patients under general anesthesia are not available, so care should be taken when considering drug therapy in cases where anesthesia is required.

The drug solution can not be used in bright light.

Do not use salt solutions as a solvent.

If the solution of the drug has spilled, it must be collected and the place wiped with a damp cloth.

Avoid contact with the mucous membrane of the eyes and skin.

After the treatment with the drug, the patient may develop temporary visual impairments (weakening of vision and visual field defects), which can interfere with his ability to drive or work with machinery. Therefore, you should avoid driving a car or working with mechanisms when developing such symptoms.

Instructions

Verteporfin (Verteporfinum)